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Derek Lowe's commentary on drug discovery and the pharma industry. An editorially independent blog from the publishers of Science Translational Medicine. All content is Derek’s own, and he does not in any way speak for his employer.

Animal Testing

Melanocortin: It’s Not Just For Lizards Any More

If you’re looking for a good example of evolution-as-a-tinkerer, the melanocortin receptors would be a good place to start. From a single starting point, they’ve ended up as a family of related proteins that do completely different things. And the hormones that bind to them have radiated out as well: they’re all derived by processing of a common precursor, pro-opiomelanocortin (POMC), and the first big split was the differentiated function of two of those cleavage products into what we would now call adrenocorticotrophic hormone (ACTH) and melanocyte-stimulating hormone (MSH). By now, humans have three forms of the latter (alpha, beta, and gamma MSH), and the receptor proteins have branched into five different MCxR subtypes as well. (Evolutionary molecular biology puts a lot of this back into roughly the lamprey/lungfish stage of things – the splits seem to have developed though gene duplication events during the periods of jawed fish and tetrapod evolution).

Along the way, they’ve each landed in their own niches. MC1R is the receptor signaling mechanism for melanin production, and is activated by MSH. The MC3R, MC4R, and MC5R receptors also respond to the different MSH subtypes in varying degrees, and these regulate things like (among others) hunger/satiety, immune response, sexual arousal, and sebaceous gland secretion – a bizarre collection indeed, which is exactly what you get after a billion years of “Hey man, whatever works”. Adding to the fun are the endogenous agouti peptides, which seem to be inverse agonists of the receptors and make their signaling ever more complex. Those have the same splits in function – agouti-signaling peptide was discovered through its effects on coat color in animals, while agouti-related peptide is a potent appetite stimulant.

This makes for quite a selectivity problem if you’re going to try to develop drugs in this area. A number of compounds have been worked on over the years, but not much has made it through, despite the marketing potential of a drug combination that could simultaneously make you lose weight, increase your sexual appetite, and give you a tan. That last one sounds fairly trivial, but it’s the target of a marketed drug, Scenesse (afamelanotide), which is a modified synthetic version of MSH. It’s administered by subcutaneous implant to people with skin pigmentation disorders, but it’s not very selective at all. Side effects (nausea, headache, decreased appetite, etc.) are quite noticeable, and since you’ve been dosed with a two-month supply, there’s not much to be done about them. (Update: I should also note bremelanotide, another MSH-like peptide with a very long and convoluted history in the clinic, which is currently heading to the FDA for a controversial female sexual dysfunction indication).

So here’s a new paper on efforts to develop a more selective MSH peptide from the same group at Arizona that discovered afamelanotide. They’d found a candidate in their earlier work, but it had several noncanonical amino acids, which slowed down potential development. The new paper is an attempt to replicate (or better) that selectivity while only using standard amino acids – in other words, to improve on nature directly. And so far, this looks possible: their new species has better selectivity than endogenous MSH, and a longer half-life in human plasma (MSH’s is five minutes, afamelanotide’s is 30 minutes, and the new species is 17 minutes).

And it certainly does the job on MC1R. Shown is an experiment on a green anole lizard (their color-changing abilities mean that they have a lot of melanocytes in their skin). Injection of afamelanotide, as shown, turns the lizard black within sixty seconds, an effect that takes two weeks to completely wear off (no doubt to the lizard’s consternation). The new peptide has exactly the same effect, but the lizard is back to his green self within 24 hours. I have to say that while I’ve had compounds go into all sorts of animal models in my career, the Ninja Lizard assay is a new one on me. The compound is still only a partial agonist (54% of maximum effect in the cell assays), but that certainly seems to be good enough, and it’s 16-fold selective for the MC1R subtype.

So this looks like a promising candidate for a second-generation therapy. If it’s safe enough, the hope is that such a drug could move into a broader market protecting people who are at are higher risk for melanoma, since darkening the skin without having to expose people to lots of UV to start with would be an ideal way to accomplish that. I’ll leave the sociological implications to others, noting only that suntans themselves have moved over the years in the Western countries from a sign of being a fieldhand, to a sign of being wealthy and leisured, to a sign (in excessive cases) of spending too much money on tanning beds and body sprays. Anole lizards no doubt have their own take.

Yes, this receptor system was great for jokes about lounge lizards even before the anoles showed up. I was surprised at no mention of Bremelanotide? It’s currently under review at the FDA…… for one of those “disorders” that makes people look askance at our industry….

It might raise some eye brows, but that is because people are conservative and uninformed. Downplaying sexual dysfunction is in fact rather cynical. It might not be a “disease” as we know it, but for some people (and couples) it is a harmful condition nonetheless.

reminds me a story of caution that I heard many years ago – it sounds just like a melanocortin drug. A peptide drug candidate was developed for some application but it turned out to be ineffective in the animal studies for the target application. However it was an effective appetite suppressant in test animals, there was a rapid weight loss and it did not show any stimulation – in fact the dogs were acting slightly cheerless. The company tried to re-purpose their candidate as a potential weight loss medication.Only when it got into human volunteers it turned out that the drug was causing headaches that contributed to the loss of appetite and the observed weight loss in the animals. The animals could not tell they have a headache, so they were just acting sulky – just like the company management afterwards.

Agouti-related peptide (AgRP )-expressing neurons are activated during starvation and have been implicated in leptin-associated infertility. AgRP expressing neurons can be also turned off and mice will exibit starvation phenotype that ensues after diphtheria toxin (DT) treatment.http://www.pnas.org/content/114/9/2413.full.pdf

Milkshaken–Typically, compounds producing non-specific suppression of feeding will have characteristic effects in one or more of the counterscreens. Drug-induced flavor aversions are pretty sensitive; the behavioral satiety sequence is a little less specific, which can be useful. One wonders if management actually ordered either of those tests on the compound you’re thinking of….

MCR1 agonists have been shown to inhibit TNF secretion in vitro and in vivo. That’s a pretty powerful immunosuppressive effect. ACTH is used clinically in MS relapse. That’s a pretty powerful immunosuppressive effect. It might just turn out that messing with that receptor is going to have a much bigger pharmacological effect than tanning your skin.

One other side point, I shudder to think of the clinical trial you suggest for prevention of melanoma. That sounds like a very long, very expensive trial. Even in a genetically susceptible patient group. Erythropoietic protoporphyria seems like a much shorter clinical trial.

“Pigmentation Study: Lizards Anolis carolinensis were purchased
from Carolina online. Peptide samples were dissolved in saline at the
concentration of 1 mM. Lizards were anesthetized by diethyl ether
before injection. The total amount of peptide was through ip injection
with 3 μg/g of each lizard. The strategy follows previous
publications.”

This post reminded me of a highly amusing article by Mac Hadley (sadly brutally murdered) recounting his labs work on MSH peptide analogues for tanning in which he self-injects (different times!) with (for the time) unintended consequences in the trouser department. My favourite passage is the following:
While I lay in bed with an emesis pan close by, I had an unrelenting erection (about 8 h duration) which could not be subdued even with a cold pack. When my wife came upon the scene, she proclaimed that I “must be crazy.” In response, I raised my arm feebly into the air and answered, “I think we may become rich.”

I can’t think of any clinical utility for this. What is the lifetime risk of melanoma? How does in compare with all the possible risks from dosing this strange drug chronically? Not to mention the undesirable aesthetics. I agree with the commenter who said a drug to block MSH would be a big seller.

And, eh, it’s a kind of slow motion train-wreck, when a senior (supposedly) scientist , get’s funny in the head on the religion and creationism, and consequently, doesn’t believe anymore in those evil ideas about receptor evolution also.